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Penile low intensity shock wave treatment for PDE5I refractory erectile dysfunction: a randomized double-blind sham-controlled clinical trial

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PurposeOver the last decade, penile low-intensity extracorporeal shockwave therapy (LI-ESWT) has emerged as a promising alternative for the treatment of erectile dysfunction (ED). The aim of this trial is to assess the effect of electromagnetic LI-ESWT on the erectile function of vascular phosphodiesterase type 5 inhibitor (PDE5I) refractory ED patients.Methods Randomized, double-blind, sham-controlled study. 76 patients with vascular PDE5I-refractory ED completed the study. 40 men were treated with LI-ESWT (1 session/week for 4 weeks, 5000 shocks/session, 0.09 mJ/mm2 energy density) and 36 were treated with a sham probe. Baseline and post-treatment (1, 3 and 6 months) evaluations were performed using validated erectile function questionnaires (IIEF-EF, EHS, SEP2, SEP3 and GAQ1). The groups were compared using Mann–Whitney–Wilcoxon and chi-squared tests, with results considered statistically significant at p < 0.05.ResultsAt the 3-month follow-up, median change in IIEF-EF score for active and sham groups was 3.5 (IQR 0–10) and − 0.5 (IQR − 11 to 1), respectively (p < 0.05). Six months after treatment, 52.5% of patients (21/40) in the active group and 27.8% of patients (10/36) in the sham group presented an EHS > 2 (p < 0.05). At the same evaluation, 40.0% (16/40) and 13.9% (5/36) of patients had positive answers to GAQ-1, in the treated and sham groups, respectively (p < 0.05). No adverse events were observed during the study.Conclusion This study showed that penile electromagnetic shockwave therapy may improve erectile function, to a modest extent, on certain patients that do not respond to PDE5I; making it an alternative for vascular ED patients that reject more invasive therapies.
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World Journal of Urology
https://doi.org/10.1007/s00345-020-03373-y
ORIGINAL ARTICLE
Penile low intensity shock wave treatment forPDE5I refractory erectile
dysfunction: arandomized double‑blind sham‑controlled clinical trial
JoseVinay1,2,3 · DanielMoreno1· OsvaldoRajmil1· EduardRuiz‑Castañe1· JosvanySanchez‑Curbelo1
Received: 12 June 2020 / Accepted: 16 July 2020
© Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract
Purpose Over the last decade, penile low-intensity extracorporeal shockwave therapy (LI-ESWT) has emerged as a promis-
ing alternative for the treatment of erectile dysfunction (ED). The aim of this trial is to assess the effect of electromagnetic
LI-ESWT on the erectile function of vascular phosphodiesterase type 5 inhibitor (PDE5I) refractory ED patients.
Methods Randomized, double-blind, sham-controlled study. 76 patients with vascular PDE5I-refractory ED completed the
study. 40 men were treated with LI-ESWT (1 session/week for 4weeks, 5000 shocks/session, 0.09mJ/mm2 energy density)
and 36 were treated with a sham probe. Baseline and post-treatment (1, 3 and 6months) evaluations were performed using
validated erectile function questionnaires (IIEF-EF, EHS, SEP2, SEP3 and GAQ1). The groups were compared using Mann–
Whitney–Wilcoxon and chi-squared tests, with results considered statistically significant at p < 0.05.
Results At the 3-month follow-up, median change in IIEF-EF score for active and sham groups was 3.5 (IQR 0–10) and
0.5 (IQR − 11 to 1), respectively (p < 0.05). Six months after treatment, 52.5% of patients (21/40) in the active group and
27.8% of patients (10/36) in the sham group presented an EHS > 2 (p < 0.05). At the same evaluation, 40.0% (16/40) and
13.9% (5/36) of patients had positive answers to GAQ-1, in the treated and sham groups, respectively (p < 0.05). No adverse
events were observed during the study.
Conclusion This study showed that penile electromagnetic shockwave therapy may improve erectile function, to a modest
extent, on certain patients that do not respond to PDE5I; making it an alternative for vascular ED patients that reject more
invasive therapies.
Keywords Erectile dysfunction· Low intensity extracorporeal shockwave therapy· Neo-angiogenesis· Nerve regeneration
Introduction
Approximately 52% of men over 40years old experience
erectile dysfunction (ED) and the prevalence of ED increases
with age [1]. Several treatments are available, including
oral phosphodiesterase type 5 inhibitors (PDE5I), vacuum
devices, intraurethral and topical alprostadil, intra-cavernous
injection therapy and penile implants [2].
There is a large number of disorders known to contrib-
ute to the development of ED, including diabetes, hypo-
gonadism, metabolic syndrome, hypertension, ischemic
heart disease, smoking, pelvic nerve injury, and local penile
abnormalities [3]. The most prevalent ED causes can be
attributed to vascular disorders, sharing multiple risk factors
with cardiovascular disease (CVD). Endothelial dysfunction
has been defined as one of the main components of both ED
and CVD pathophysiology [4].
Traditional treatments carry risks of adverse events
and complications, and most available treatments take the
spontaneity out of sex [1]. Furthermore, these modalities
are solely providing symptom relief and do not provide a
permanent improvement by targeting underlying pathophysi-
ological events [3].
Over the last decade, penile low-intensity extracorporeal
shockwave therapy (LI-ESWT) has emerged as a promis-
ing option for the treatment of ED [5]. Originally used to
* Jose Vinay
jose.vinay@gmail.com
1 Andrology Department, Fundació Puigvert/Universidad
Autònoma de Barcelona, Carrer de Cartagena,
340-350,08025Barcelona, Spain
2 Urology Department, University ofChile Clinical Hospital,
Santiago, Chile
3 Andrology Unit, Shady Grove Fertility, Santiago, Chile
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World Journal of Urology
1 3
treat other conditions like bone fractures, musculoskeletal
disorders, CVD and chronic wounds; LI-ESWT already has
been used in ED protocols all over the world [6]. The exact
mechanism of action of LI-ESWT is still not completely elu-
cidated, but energy from the acoustic waves is hypothesized
to activate cellular pathways that increase the expression of
local growth factors, improving endothelial function, angio-
genesis and potentially regenerating nerve fibers [1, 7].
There has been a low number of sham-controlled ran-
domized trials, and only one of them has presented data
regarding ED patients that do not respond to PDE5I therapy
[3]. The current study aimed to assess the effect of LI-ESWT
on vascular PDE5I-refractory ED patients in a sham-con-
trolled manner.
Materials andmethods
This is a prospective, randomized, double-blind, sham con-
trolled study of 80 men with PDE5I-refractory ED. They
were randomized on a 1:1 ratio to LI-ESWT (n = 40) or sham
treatment (n = 40). All patients completed the study protocol
in the active LI-ESWT group. There were 4 dropouts in the
sham group. This study was reviewed and approved by the
Institutional Ethics Review Board. Participants provided
written informed consent before enrolling in the study.
Inclusion andexclusion criteria
All participants included in this study were recruited from
the Andrology Clinic of a University Hospital. They pre-
sented a history of ED of more than 6months not respond-
ing to PDE5I drugs. PDE5I non-responders were defined
as patients with an inadequate erectile response after at
least four attempts using the highest tolerated drug [8]. All
patients were correctly treated with on-demand use of at
least two of the following drugs: sildenafil 100mg, tadalafil
20mg or vardenafil 20mg.
At baseline all patients had an International Index of
Erectile Function–Erectile Function domain (IIEF-EF)
score < 26. Men were excluded from the study if they had
any penile anatomical abnormality, an unstable medical
condition, neurological/hormonal abnormalities, history
of pelvic surgery/radiotherapy, current use of psychotropic
drugs or a diagnosis of a specific ED etiology different to
vascular ED.
Study protocol
At the first visit, patients were evaluated with IIEF-EF and
Erection Hardness Score (EHS) questionnaires as well as
the Questions 2 and 3 of the Sexual Encounter Profile (SEP2
and SEP3). Patients who met study inclusion criteria were
assigned in a 1:1 ratio (using a randomization software) to
the active LI-ESWT group and the sham group. Each sub-
ject then began the 4-week treatment protocol. The protocol
included 1 session per week for 4weeks. The safety of the
LI-ESWT was monitored throughout the study and adverse
events were evaluated in each visit. Response to therapy was
measured 1, 3 and 6months after the last session using IIEF-
EF, EHS, SEP2, SEP3 and the Global Assessment Question
(GAQ1). All patients stopped using ED drugs during study
protocol and follow-up, with a wash-out period of 2months.
In each of the four LI-EWST sessions and three post-treat-
ment evaluations, patients were questioned about the use of
ED drugs.
LI‑EWST specications
Patients were treated with the RENOVA® electromagnetic
device (Direx Group, Wiesbaden, Germany) which produces
linear low intensity shock waves (0.09mJ/mm2 with a fre-
quency of 120 shock waves per minute). Each session com-
prised 5000 pulses using a specialized probe divided in 4
foci: 900 shocks to each corpora cavernosa and 1600 shocks
to each crus. No analgesia was needed. When treating the
control group, the device probe was replaced with one that
had the same shape, weight and sound, but did not generate
shockwaves. Both patient and probe operator were blind to
the procedure.
Outcome measures
The primary outcome measurement was the median change
of IIEF-EF score from baseline. Secondary outcome
measurements consisted of percentage of patients with an
EHS > 2 (which indicates the penis is hard enough for pene-
tration) and with positive answers to SEP2, SEP3 and GAQ1
questions. All of the erectile function (EF) questionnaires
were applied at baseline and during the three post-treatment
evaluations (1, 3 and 6months after final session).
Statistical analysis
Quantitative parameters were presented as medians with
interquartile range (IQR) and compared between the groups
using Mann–Whitney–Wilcoxon test. The change of IIEF-
EF scores has been used by several authors to compare LI-
ESWT effects between active and sham treated patients [9,
10]. Linear regression analysis was performed on IIEF-EF
results. Qualitative parameters were shown as absolutes
numbers and percentages. The groups were compared
using the Chi-square test. Sample size was calculated to
detect a change in IIEF-EF score of 4 points at 80% power.
All results with p < 0.5 considered statistically significant.
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World Journal of Urology
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SPSS® software (IBM Statistics, Armonk, New York, USA)
was used for analysis.
Results
In the active LI-ESWT and sham groups 40 and 36 patients,
respectively, completed the study. Table1 shows the base-
line parameters for both groups, with no statistically sig-
nificant differences between them. Subjects were, predomi-
nantly, middle-aged men with a high prevalence of multiple
cardiovascular risk factors. Both active and sham groups
were consisting of patients with largely moderate ED, with
median IIEF-EF scores of 12 (IQR 8–17) and 13 (IQR
8–17), respectively.
There were not significant differences in EF questionnaire
scores between groups at the 1-month follow up evaluation
(Table2). The median change in IIEF-EF domain score was
1 (IQR − 1 to 6) in the active group and 0 (IQR − 8 to 4) in
the sham group (p = 0.066). No significant differences were
observed between groups regarding the percentage of men
with an EHS > 2 or the number of positive answers to SEP2,
SEP3 and GAQ1 during the first month evaluation.
At the 3-month follow-up, there was a median change in
IIEF-EF score of 3.5 (IQR 0–10) and − 0.5 (IQR − 11 to 1)
in the active and sham groups, respectively (p = 0.004). Dif-
ferences between patients with EHS > 2 or positive answers
to SEP2, SEP3 and GAQ1 were not significant at this spe-
cific time-point.
The percentage of subjects in the active group that
described an EHS > 2 showed an increasing trend through
the study (Fig.1).
At the 6-month follow-up, the proportion of patients
with EHS > 2 was 52.5% (21/40) in the LI-ESWT group
and 27.8% (10/36) in the sham group (p = 0.028). Patients
with positive answers to GAQ-1 were 16/40 (40.0%) and
5/36 (13.9%) in the active and sham groups, respectively
(p = 0.011). SEP2 and SEP3 positive answers did not present
significant differences between groups in any of the follow-
up evaluations (Table2).
Linear regression analyses adjusted for baseline param-
eters was performed on IIEF-EF changes. It showed that
being in the active treatment group is predictive of a higher
Table 1 Baseline characteristics of study population at randomization
ED Erectile dysfunction, BMI Body mass index, IIEF-EF Interna-
tional Index of Erectile function–erectile function domain, EHS Erec-
tion hardness score, SEP-2 Question 2 of the sexual encounter profile,
SEP-3 Question 3 of the sexual encounter profile
Active Sham p-value
Number of patients 40 36
Median age [years] (IQR) 60 (54–66) 60 (53–65) 0.826
Median ED duration [years]
(IQR)
3 (2–6) 4.5 (3–6) 0.099
Median BMI [kg/m2] (IQR) 27 (25–30) 28 (26–29.8) 0.313
Cardiovascular risk factors (%)
Diabetes mellitus 12 (30.0%) 11 (30.6%) 1.000
Ischemic heart disease 1 (12.5%) 4 (11.1%) 0.184
Hypertension 23 (57.5%) 27 (75.0%) 0.491
Dyslipedemia 14 (35.0%) 19 (52.8%) 0.165
Median IIEF-EF score (IQR) 12 (8–17) 13 (8–17) 0.352
Median EHS (IQR) 2 (1–3) 2 (1–3) 0.478
Patients with positive SEP-2
(%)
17 (42.5%) 19 (52.8%) 0.491
Patients with positive SEP-3
(%)
6 (15.0%) 8 (22.2%) 0.556
Table 2 Post-treatment erection function parameters
IIEF-EF International Index of Erectile Function–Erectile Func-
tion domain, EHS Erection hardness score, SEP-2 Question 2 of the
Sexual Encounter Profile, SEP-3 Question 3 of the Sexual Encounter
Profile
*p < 0.05
Active Sham p-value
Median IIEF-EF score (IQR)
Baseline 12 (8–17) 13 (8–17) 0.352
1 month 11 (8–20) 10 (6–19)
Change 1 (− 1–6) 0 (− 8–4) 0.066
3 months 15 (9–23) 9 (5–21)
Change 3.5 (0–10) − 0.5 (− 11–1) 0.004*
6 months 15 (7–22) 8 (6–17)
Change 1 (− 1–7) 0 (− 4–2) 0.246
Patients with EHS >2
Baseline 13 (32.5%) 14 (38.9%) 0.561
1 month 18 (45.0%) 12 (33.3%) 0.378
3 months 18 (45.0%) 15 (41.7%) 0.807
6 months 21 (52.5%) 10 (27.8%) 0.028*
Patients with positive SEP-2
(%)
Baseline 17 (42.5%) 19 (52.8%) 0.491
1 month 23 (57.5%) 21 (58.3%) 0.884
3 months 18 (45.0%) 22 (61.1%) 0.258
6 months 21 (52.5%) 20 (55.6%) 0.821
Patients with positive SEP-3
(%)
Baseline 6 (15.0%) 8 (22.2%) 0.556
1 month 9 (22.5%) 8 (22.2%) 0.762
3 months 12 (30.0%) 11 (30.6%) 0.864
6 months 11 (27.5%) 5 (13.9%) 0.146
Patients with positive GAQ-1
(%)
1 month 15 (37.5%) 14 (38.9%) 0.878
3 months 18 (45.0%) 11 (30.6%) 0.342
6 months 16 (40.0%) 5 (13.9%) 0.011*
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World Journal of Urology
1 3
magnitude of IIEF-EF increase with a β coefficient of 3.44
[95%Confidence interval 0.23–6.57] (p = 0.028).
There were not any adverse events described by the par-
ticipants, in neither group, during the 4-week treatment or
the 6-month follow up period.
Discussion
Although LI-ESWT has been studied for more than a dec-
ade in ED patients, this is still a controversial therapy with
different degrees of recommendation depending on the
specific clinical guideline of scientific societies [11]. For
example, position statements and clinical guidelines from
the American Urological Association, the European Soci-
ety of Sexual Medicine and the Sexual Medicine Society of
North America recommend that LI-ESWT should be con-
sidered an experimental therapy and be used under research
protocols [1113]. On the other hand, for the first time the
European Association of Urology in their 2020 Guidelines
recommend the use of LI-ESWT as a first-line therapy for
mild vasculogenic ED [14] clearly acknowledging the recent
evidence supporting the use of shockwave therapy in this
specific ED etiology.
In the last 10years, several invitro and animal trials
have shown that LI-ESWT may improve EF through neo-
angiogenesis, recruitment of progenitor cells, modulation of
vasodilation and nerve regeneration [1, 1518]. It seems that
LI-EWST induces synthesis of pro-angiogenic factors and
chemokines [19]. Other studies have exhibited the effects of
LI-ESWT on restoring normal penile histology after pelvic
neurovascular damage [20].
The current study shows a modest improvement in EF
parameters after 3 and 6months following penile shockwave
therapy. Median change in IIEF-EF scores are significantly
higher in the active group after 3months of LI-ESWT. The
decrease of control group scores could be explained because
subjects do not experience any improvements and become
gradually frustrated without being able to use PDE5I. At
6months of follow-up, the proportion of patients with
EHS > 2 and the number of patients that feel that LI-ESWT
improved their EF (positive answer to GAQ-1) is signifi-
cantly higher in the active group (Table2). The significant
difference in penile rigidity between the two groups (Fig.1)
is relevant, as other authors have considered the EHS one of
the most robust parameters to evaluate EF [11].
These results are similar to the ones presented in other
clinical trials. However, studies differ in ED etiology, type
of device used (source of energy, focal vs linear), shockwave
protocol (duration, energy intensity, number and frequency
of shocks) and patient-reported outcomes evaluated [3, 11].
Moreover, several studies have important limitations, drop-
out rates and biases, making it difficult to draw conclusions
or recommendations from those results [11, 21].
The optimal patient and treatment protocol are yet to be
determined. It appears that more shocks and stronger shocks
typically lead to greater improvements in EF [22]. Linear
distribution of shockwaves may provide a better coverage
of the corpora cavernosa than focal devices thus improving
treatment outcomes [3].
To this date, there is only 13 randomized placebo con-
trolled clinical trials investigating LI-ESWT as a treatment
for ED [9, 10, 21, 2331]. Additionally, there has been
five meta-analyses published regarding LI-ESWT studies
[3236]. Some of them have not excluded studies at high
risk of bias or have included studies with equivocal data.
Since the studies most burdened with a high risk of bias also
have the largest reported effects size, the inclusion of these
trials distorts the results of meta-analyses towards positive
results for LI-ESWT compared to placebo [3]. Taking the
five recent meta-analyses into account, and in spite of meth-
odological flaws, most of these analyses report a modest
Fig. 1 Percentage of patients
with EHS > 2. EHS erection
hardness score, LI-ESWT
low-intensity extracorporeal
shockwave therapy. *p < 0.05
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World Journal of Urology
1 3
statistically significant benefit for active treatment vs pla-
cebo group. IIEF-EF improvements of 2.00, 2.54 and 4.57
are presented in the Lu etal., Angulo etal. and Clavijo etal.
meta-analyses, respectively [1, 32, 34, 35].
This study has been designed because PDE5I non-
responders are seldomly considered in shockwave studies
[35]. There is only one sham-controlled randomized clinical
trial that has included the same PDEI-refractory population
as in the current study. In 2016 Kitrey etal. conducted a
randomized study on a small sample of 55 refractory ED
patients (active group = 37, sham group = 18) with only
1month of follow-up. The median change from baseline in
the IIEF-EF score was 5 points in the treatment group and
0 points in the sham treatment group (P = 0.0006), while
the percentage of EHS = 3 patients was 54% in the active
group vs 0% in the sham group (P < 0.0001) [9, 11]. In this
study, LI-ESWT effect was evaluated only during obliga-
tory PDE5I treatment. They aimed to convert PDE5I non-
responders into responders. The current study aims to show
the changes in several EF parameters without using any ED
drugs. This pivotal difference makes the comparison of both
studies difficult.
Several clinical guidelines still consider shockwaves as
an experimental therapy [11, 13]. This could be explained
by the high level of heterogeneity and risk of biases of pub-
lished clinical trials. Meta-analyses currently available show
important methodological flaws, by including unpublished
data, studies at high risk of bias, studies with ED as a sec-
ondary end point, non-randomized trials [1] and incorrect
citation of IIEF data (confusion of IIEF with IIEF-EF) [37].
The current clinical trial shows that this specific linear
electromagnetic shockwave protocol may improve EF, to a
modest extent, on certain patients that do not respond to oral
therapy. Hence, it could be an alternative for vascular ED
patients that do not respond to traditional first line PDE5I
and reject more invasive therapies.
The study has several limitations. There was a limited
sample size; however, this is common among LI-ESWT
clinical trials. Penile hemodynamics were not measured to
diagnose vasculogenic ED or to confirm the improvement
of cavernous blood inflow or penile rigidity. Penile doppler
ultrasound could be considered to measure arterial inflow
and venous outflow. Although 6months of follow-up is
higher than the duration of several other trials, > 1year of
follow-up would be better to correctly assess the long-term
effects of this therapy.
Conclusion
This randomized double-blind sham-controlled trial showed
moderate improvement in different EF parameters at 3 and
6months of follow-up. It is of the utmost importance to
elaborate randomized sham-controlled studies with long fol-
low ups, that compare different ED etiologies and protocol
characteristics, to elucidate the real role of LI-EWST in the
treatment of ED.
Author contributions JV: project development, data collection, data
analysis, manuscript writing. DM: data collection. OR: project devel-
opment. ER-C: project development. JS-C: project development, data
collection, manuscript writing
Compliance with ethical standards
Conflicts of interest The researchers received materials for the LI-
EWST device from the manufacturer (Direx Group, Wiesbaden, Ger-
many) to carry out the clinical trial. No special funding was received.
Research involving human participants and/or animals This study was
reviewed and approved by Fundació Puigvert Ethics Review Board:
(FP-ANDRO-2016/01).
Informed consent Participants provided written informed consent
before enrolling in the study.
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... Since that time, multiple retrospective, single-arm prospective, and randomized-controlled trials have been published. This includes 11 randomized, sham-controlled trials evaluating the impact of LiSWT on men with vasculogenic ED ( Table 2) (32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42). Results are somewhat mixed owing in part to differences in patient populations, study design, outcomes assessed, follow-up duration, and the type of shockwave technology utilized. ...
... I n t o t a l , 7 / 1 1 ( 6 4 % ) s h a m -c o n t r o l l e d t r i a l s showed a statistically significant increase in IIEF scores in the treatment arm when compared with the control arm. IIEF scores (either IIEF-EF or IIEF-5) in the treatment arm ranged from +1-12.5 points, depending on the specific study (32,35,36,(38)(39)(40)(41)(42). 3/11 trials (27%) did not show a benefit favoring LiSWT over sham (33,34,37). ...
... At least 11 randomized, sham-controlled trials have sought to evaluate treatment outcomes, with >60% showing a statistically significant i n c r e a s e i n I I E F s c o r e s f a v o r i n g L i S W T ( m e a n improvement ranging from 1-12.5 points). Studies in other populations such as those with pelvic surgery have shown a benefit as well (35,44). To this end, of the at least eight available meta-analyses, all have supported a statistically significant increase in IIEF-scores with LiSWT (46)(47)(48)(49)(50)(51)(52)(53). ...
... Of the remaining 39 articles, 23 articles were excluded because they are not RCT or lack of effective data. Finally, the remaining 16 articles were included in the study to evaluate the effectiveness of LI-ESWT in the treatment of ED (Baccaglini et al., 2020;Fojecki et al., 2017;Kalyvianakis & Hatzichristou, 2017;Kim et al., 2020;Kitrey et al., 2016;Ladegaard et al., 2021;Olsen et al., 2015;Ortac et al., 2021;Shendy et al., 2021;Sramkova et al., 2020;Srini et al., 2015;Vardi et al., 2012;Vinay et al., 2021;Yamaçake et al., 2019;Yee et al., 2014;Zewin et al., 2018). The details of each study are presented in Table 1. ...
Article
Full-text available
We conducted a meta-analysis to evaluate the efficacy of low-intensity extracorporeal shock wave therapy (LI-ESWT) in the treatment of erectile dysfunction (ED). From July 2011 to June 2021, we finally selected 16 randomized controlled trials (RCTs) including 1,064 participants to evaluate the efficacy of LI-ESWT in the treatment of ED from PubMed, EMBASE, and Cochrane databases. The data are analyzed by Review Manager Version 5.4. Fifteen articles mentioned International Index of Erectile Function (IIEF), in the follow-up of 1 month (mean difference [MD] = 3.18, 95% confidence interval [CI] = [1.38, 4.98], p = .0005), 3 months (MD = 3.01, 95% CI = [2.04, 3.98], p < .00001), and 6 months (MD = 3.20, 95% CI = [2.49, 3.92], p < .00001). After treatment, the improvement of IIEF in the LI-ESWT group was better than that in the control group. Besides, eight of the 16 trials provided data on the proportion of patients with baseline Erectile Hardness Score (EHS) ≤ 2 improved to EHS ≥ 3. The LI-ESWT group was also significantly better than the placebo group (odds ratio [OR] = 5.07, 95% CI = [1.78, 14.44], p = .002). The positive response rate of Questions 2 and 3 of the Sexual Encounter Profile (SEP) was not statistically significant (SEP2: OR = 1.27, 95% CI = [0.70, 2.30], p = .43; SEP3: OR = 4.24, 95% CI = [0.67, 26.83], p = .13). The results of this meta-analysis suggest that treatment plans with an energy density of 0.09 mJ/mm ² and pulses number of 1,500 to 2,000 are more beneficial to IIEF in ED patients. In addition, IIEF improvement was more pronounced in patients with moderate ED after extracorporeal shockwave therapy.
... 8,9 In particular, LiST may augment treatment response by acting synergically to tadalafil. 10,11 Based on the previous notion, LiST induces shear stress and endothelial damage which, in turn, leads to neoangiogenesis of the corporal tissue. 12 In this setting, it has been suggested that daily tadalafil may further increase blood supply and enhance the efficacy of LiST and vice versa. ...
Article
Background Combination of different first-line treatments for erectile dysfunction (ED) has emerged as a promising therapeutic approach. Aim To conduct the first double-blind, randomized, placebo-controlled clinical trial to evaluate the efficacy and safety of combination therapy with low-intensity shockwave therapy (LiST) and tadalafil vs LiST and placebo in patients with mild or mild-to-moderate vasculogenic ED. Methods Fifty sexually active patients fulfilling the eligibility criteria were randomly assigned to 6 sessions of LiST twice weekly for 3 weeks and tadalafil (n = 25) or placebo (n = 25) once daily for 4 weeks. Patients were evaluated at 1, 3, and 6 months after completion of the treatment protocol. Outcomes The primary outcome was the mean change from baseline in the International Index of Erectile Function-Erectile Function (IIEF-EF) domain between the 2 groups at 3 months after treatment. Erectile function was also assessed at 1 and 6 months. The number of patients attaining a minimal clinically important difference (MCID) in the IIEF-EF, as well as the safety of combination therapy were evaluated. Results Adjusting for the baseline values, IIEF-EF improved by 0.8 points more (95% confidence interval [CI] = −0.2 to 1.9, P = .12) at 1 month, 1 point more (95% CI = 0.1–1.9, P = .02) at 3 months and 1.7 points more (95% CI = 0.8–2.7, P < .001) at 6 months in patients treated with combination therapy compared to monotherapy. The number of patients attaining a MCID in the IIEF-EF between the 2 groups improved significantly only at the 3-month evaluation. No adverse events were reported during the whole study period. Clinical Implications Combination of LiST twice weekly for 3 weeks and tadalafil 5 mg once daily for 4 weeks may further ameliorate mild or mild-to-moderate vasculogenic ED compared to LiST monotherapy. Strengths & Limitations We conducted the first randomized trial exploring the role of LiST and tadalafil in the management of ED. Conversely, our study lacks external validity due to its single-center design. Conclusion The addition of daily low-dose tadalafil during application of LiST may further improve erectile function compared to application of LiST as a standalone treatment in patients with mild or mild-to-moderate vasculogenic ED. Still, further high-quality studies are warranted to corroborate our findings. Mykoniatis I, Pyrgidis N, Zilotis F, et al. The Effect of Combination Treatment With Low-Intensity Shockwave Therapy and Tadalafil on Mild and Mild-To-Moderate Erectile Dysfunction: A Double-Blind, Randomized, Placebo-Controlled Clinical Trial. J Sex Med 2021;XX:XXX–XXX.
Article
Full-text available
A shock wave (SW), which carries energy and propagates through a medium, is a type of continuous transmitted sonic wave that can achieve rapid energy transformations. SWs have been applied for many fields of medical science in various treatment settings. In urology, high-energy extracorporeal SWs have been used to disintegrate urolithiasis for 30 years. However, at lower energy levels, SWs enhance the expression of vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), proliferating cell nuclear antigen (PCNA), chemoattractant factors, and the recruitment of progenitor cells, and inhibit inflammatory molecules. Low energy extracorporeal shock wave (LESW) therapy has been used in urology for treating chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), interstitial cystitis/bladder pain syndrome (IC/BPS), overactive bladder, stress urinary incontinence, and erectile dysfunction through the mechanisms of anti-inflammation, neovascularization, and tissue regeneration. Additionally, LESW have been proven to temporarily increase tissue permeability and facilitate intravesical botulinum toxin delivery for treating overactive bladders in animal studies and in a human clinical trial. LESW assisted drug delivery was also suggested to have a synergistic effect in combination with cisplatin to improve the anti-cancer effect for treating urothelial cancer in an in vitro and in vivo study. LESW assisted drug delivery in uro-oncology is an interesting suggestion, but no comprehensive clinical trials have been conducted as of yet. Taken together, LESW is a promising method for the treatment of various diseases in urology. However, further investigation with a large scale of clinical studies is necessary to confirm the real role of LESW in clinical use. This article provides information on the basics of SW physics, mechanisms of action on biological systems, and new frontiers of SW medicine in urology.
Article
Energy-based therapies are novel treatments for erectile dysfunction that are thought to work by stimulation of tissue vasodilation, neoangiogenesis, and so forth. Low-intensity extracorporeal shock wave therapy (Li-ESWT) is the energy-based therapy with the most robust evidence basis demonstrating efficacy and safety. Among this evidence, randomized controlled trials (RCTs) evaluating Li-ESWT have largely been focused on responders to phosphodiesterase-5 inhibitors. Many of these RCTs have limitations including short follow-up durations, inconsistent protocols, and small sample sizes. Until more diverse patient populations are studied and these limitations are addressed, the use of Li-ESWT should remain limited to IRB-approved clinical research trials.
Article
Context: The present summary of the European Association of Urology (EAU) guidelines is based on the latest guidelines on male sexual health published in March 2021, with a last comprehensive update in January 2021. Objective: To present a summary of the 2021 version of the EAU guidelines on sexual and reproductive health. Evidence acquisition: A literature review was performed up to January 2021. The guidelines were updated, and a strength rating for each recommendation was included based on either a systematic review of the evidence or a consensus opinion from the expert panel. Evidence synthesis: Late-onset hypogonadism is a clinical condition in the ageing male combining low levels of circulating testosterone and specific symptoms associated with impaired hormone production and/or action. A comprehensive diagnostic and therapeutic work-up, along with screening recommendations and contraindications, is provided. Erectile dysfunction (ED) is the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance. Along with a detailed basic and advanced diagnostic approach, a novel decision-making algorithm for treating ED in order to better tailor therapy to individual patients is provided. The EAU guidelines have adopted the definition of premature ejaculation (PE), which has been developed by the International Society for Sexual Medicine. After the subtype of PE has been defined, patient's expectations should be discussed thoroughly and pharmacotherapy must be considered as the first-line treatment for patients with lifelong PE, whereas treating the underlying cause must be the initial goal for patients with acquired PE. Haemospermia is defined as the appearance of blood in the ejaculate. Several reasons of haemospermia have been acknowledged; the primary goal over the management work-up is to exclude malignant conditions and treat any other underlying cause. Conclusions: The 2021 guidelines on sexual and reproductive health summarise the most recent findings, and advise in terms of diagnosis and treatment of male hypogonadism and sexual dysfunction for their use in clinical practice. These guidelines reflect the multidisciplinary nature of their management. Patient summary: Updated European Association of Urology guidelines on sexual and reproductive health are presented, addressing the diagnosis and treatment of the most prevalent conditions in men. Patients must be fully informed of all relevant diagnostic and therapeutic options and, together with their treating physicians, decide on optimal personalised management strategies.
Article
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Purpose of Review Focused extracorporeal shockwave therapy (fESWT) is a physical treatment modality developed over the last 25 years for musculoskeletal indications. It has many indications in the field of physical medicine and rehabilitation (PM&R) and is effective, time-efficient, and cost-efficient. This review focuses on basics and on clinical indications as well as on significant trends in fESWT. Recent Findings In PM&R, stimulation of healing processes in tendons, surrounding tissue, and bones via mechanotransduction seems to be a relevant biological effect. The International Society for Medical Shockwave Treatment (ISMST) describes different types of indications (such as approved standard indications—in accordance with most scientific evidence—like calcifying tendinopathy of the shoulder, plantar fasciitis lateral epicondylopathy of the elbow, greater trochanter pain syndrome, patellar tendinopathy, Achilles tendinopathy and bone non-union, common empirically tested clinical uses, exceptional or expert indications, and experimental indications). Summary fESWT is a relevant treatment option in PM&R and regenerative medicine. In recent years, historical paradigms (for example, application in cancer patients) have changed and new indications (such as nerve regeneration, myofascial trapezius syndrome, low back pain, dermatosclerosis, and lymphedema) are supported. Future translational research should focus on establishing actual exceptional indications and experimental indications for clinical routine.
Article
Full-text available
Introduction: Low-intensity extracorporeal shock wave therapy (Li-ESWT) is a new treatment modality for erectile dysfunction (ED). Our aim was to evaluate the treatment outcome of Li-ESWT for ED in single-blind, placebo controlled, randomized clinical trial. Methods: Sixty patients were randomized into 2 age-matched groups: Group A - treatment and Group B - placebo. Treatment consisted of 4 sessions on the PiezoWave2 unit (R. Wolf and ELvation Medical). Effectiveness was assessed according to the International Index of Erectile Function 5 (IIEF-5), Erectile Hardness Score (EHS), questions 2 and 3 of the Sexual Encounter Profile (SEP 2, SEP 3), and Global Assessment Question (GAQ) scores at baseline and 4 and 12 weeks after treatment. We evaluated patient's and partner's subjective satisfaction. Results: A statistically significant difference between the groups was found at 4 and 12 weeks after treatment with regard to the quality of erection as measured by the IIEF-5 (p = 0.049 and p < 0.001, respectively), the EHS after week 12 (p < 0.001), an increase in the EHS after 4 and 12 weeks (p = 0.030 and p < 0.001, respectively), after 12 weeks in GAQ (p < 0.001), SEP 2 (p = 0.05), SEP 3 (p < 0.001), and patient's satisfaction (p < 0.001) and partner's satisfaction (p < 0.001). Conclusions: The randomized single-blind study confirms that Li-ESWT significantly improves erectile function.
Article
Full-text available
Objectives: To study the efficacy of Low intensity Extracorporeal Shockwave Therapy (Li- ESWT) for the treatment of erectile dysfunction (ED) in kidney transplanted men. Methods: Twenty men (mean age = 53.7 years) were selected. This was a double-blinded, prospective, randomized, sham-controlled trial. The ESWT protocol was based in a 2 treatment sessions per week for 3 weeks. The sham treatment was performed using the same device replacing the effective probe for one that emits zero energy. Baseline and follow-up assessment was performed with International Index of Erectile Function Questionnaire (IIEF) score and Erection Hardness Score (EHS) after 1, 4 and 12 months. Penile Doppler was performed before and after treatment. Results: A total of 20 patients were recruited, 10 patients in each group. Baseline scores were similar. The mean EHS in after 1 month were 2.5 ± 0.85 (Li-EWST) and 2.4 ± 0.7 (Sham therapy), p = 0.724 . After 4 months it was 2.4 ± 0.7 and 2.6 ± 0.84, p = 0,0004 (between the moments) . The baseline IIEF score was 14.9 ± 3(Sham Theraphy) and 10.9 ± 5.1 (Li-EWST). The mean IIEF score after 1 month was 15.6 ± 6.1 (Li-EWST) and 16.6 ± 5.4 (Sham therapy). The mean IIEF score after 4 months was 17.2 ± 5.7 (Li-EWST) and 16.5 ± 5 (Sham therapy), p < 0.0001 (between the moments). IIEF score improvement was higher than 5 in 70% (ranged from 0-10) and in 10% (ranged from 1-14) in Li-ESWT and Sham groups, respectively. The mean change in IIEF score after 12 months was 4.8 in Li-ESWT group .Penile Doppler parameters were similar between groups and did not present improvements. Conclusions: Li-ESWT is a treatment with clinical efficacy. Despite evidences suggesting neoagiogenesis, our short protocol had no impact in penile Doppler parameters.
Article
Full-text available
Purpose: The purpose of this guideline is to provide a clinical strategy for the diagnosis and treatment of erectile dysfunction. Materials & methods: A systematic review of the literature using the Pubmed, Embase, and Cochrane databases (search dates 1/1/1965 to 7/29/17) was conducted to identify peer-reviewed publications relevant to the diagnosis and treatment of erectile dysfunction. Evidence-based statements were based on body of evidence strength Grade A, B, or C and were designated as Strong, Moderate, and Conditional Recommendations with additional statements presented in the form of Clinical Principles or Expert Opinions. Results: The American Urological Association has developed an evidence-based guideline on the management of erectile dysfunction. This document is designed to be used in conjunction with the associated treatment algorithm. Conclusions: Using the shared decision-making process as a cornerstone for care, all patients should be informed of all treatment modalities that are not contraindicated, regardless of invasiveness or irreversibility, as potential first-line treatments. For each treatment, the clinician should ensure that the man and his partner have a full understanding of the benefits and risk/burdens associated with that choice.
Article
Full-text available
Introduction: Short-term data on the effect of low-intensity extracorporeal shockwave therapy (Li-ESWT) on erectile dysfunction (ED) have been inconsistent. The suggested mechanisms of action of Li-ESWT on ED include stimulation of cell proliferation, tissue regeneration, and angiogenesis, which can be processes with a long generation time. Therefore, long-term data on the effect of Li-ESWT on ED are strongly warranted. Aim: To assess the outcome at 6 and 12 months of linear Li-ESWT on ED from a previously published randomized, double-blinded, sham-controlled trial. Methods: Subjects with ED (N = 126) who scored lower than 25 points in the erectile function domain of the International Index of Erectile Function (IIEF-EF) were eligible for the study. They were allocated to 1 of 2 groups: 5 weekly sessions of sham treatment (group A) or linear Li-ESWT (group B). After a 4-week break, the 2 groups received active treatment once a week for 5 weeks. At baseline and 6 and 12 months, subjects were evaluated by the IIEF-EF, the Erectile Hardness Scale (EHS), and the Sexual Quality of Life in Men. Main outcome measures: The primary outcome measure was an increase of at least 5 points in the IIEF-EF (ΔIIEF-EF score). The secondary outcome measure was an increase in the EHS score to at least 3 in men with a score no higher than 2 at baseline. Data were analyzed by linear and logistic regressions. Results: Linear regression of the ΔIIEF-EF score from baseline to 12 months included 95 patients (dropout rate = 25%). Adjusted for the IIEF-EF score at baseline, the difference between groups B and A was -1.30 (95% CI = -4.37 to 1.77, P = .4). The success rate based on the main outcome parameter (ΔIIEF-EF score ≥ 5) was 54% in group A vs 47% in group B (odds ratio = 0.67, P = .28). Improvement based on changes in the EHS score in groups A and B was 34% and 24%, respectively (odds ratio = 0.47, P = .82). Conclusion: Exposure to 2 cycles of linear Li-ESWT for ED is not superior to 1 cycle at 6- and 12-month follow-ups. Fojecki GL, Tiessen S, Osther PJS. Effect of Linear Low-Intensity Extracorporeal Shockwave Therapy for Erectile Dysfunction-12-Month Follow-Up of a Randomized, Double-Blinded, Sham-Controlled Study. Sex Med 2017;X:XXX-XXX.
Article
Background: Erectile dysfunction (ED) after radical prostatectomy (RP) still represents a major issue. Considering the benefits recently described regarding the application of low-intensity extracorporeal shockwave therapy (LiESWT) in vasculogenic ED, questions arise about its role in the scenario of penile rehabilitation. Aim: To compare the early introduction of phosphodiesterase-5 inhibitor (PDE5i) with a combination therapy enrolling both early PDE5i use and LiESWT in patients submitted to RP. Methods: This study is a randomized clinical trial, open-label, with 2 parallel arms and an allocation ratio of 1:1. The study was registered in ReBEC (ensaiosclinicos.gov.br) Trial: RBR-85HGCG. Both arms started tadalafil at a dose of 5 mg/day right after the removal of the transurethral catheter, and the experimental group received 2,400 shocks/session-week distributed on 4 different penile regions. The full treatment consisted of 19,200 impulses across 8 weeks. Outcomes: The primary clincal end point was ≥4-point difference favoring the experimental group considering the mean International Index of Erectile Function short form (IIEF-5) at last follow-up. Any statistical difference in the IIEF-5 score between the arms was stated as the primary statistical end point. Results: Between September 25, 2017, and December 3, 2018, 92 men were enrolled in the study. At last follow-up, we assessed 77 patients, 41 in the control group and 36 in the intervention group. A difference between groups was detected when accessing the final median IIEF-5 score (12.0 vs 10.0; P = .006). However, the primary clinical endpoint considering a difference ≥4-point between the arms has not been reached. When performing an exploratory analysis comparing the proportion of those individuals with an IIEF-5 score ≥17, no difference between groups was noted (17.1% vs 22.2%; P = .57). Clinical implications: So far, the benefits arising from LiESWT for penile rehabilitation after RP have been uncertain. Strengths & limitations: This is the first trial assessing the role of LiESWT on erectile function after RP. Our study protocol included only one session per week for the experimental group, raising a query if a more intensive application could achieve better results once a statistically significant difference was found between groups. We discontinue the PDE5i use at the last session, which may have interfered in the penile vascular rehabilitation, maybe compromising the results too. Conclusion: After therapy with 19,200 impulses therapy across 8 weeks, we found an improvement of the IIEF-5 score, but it was not enough to be considered clinically significant. More studies are warranted before any recommendation on this topic. Baccaglini W, Pazeto CL, Corrêa Barros EA, et al. The Role of the Low-Intensity Extracorporeal Shockwave Therapy on Penile Rehabilitation After Radical Prostatectomy: A Randomized Clinical Trial. J Sex Med 2020;XX:XXX-XXX.
Article
Introduction: Low-intensity shockwave therapy (LISWT) has been investigated for the treatment of uroandrological disorders including erectile dysfunction (ED), Peyronie's disease (PD) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) with controversial findings. Aim: To review the evidence on LISWT for ED, PD, and CP/CPPS and provide clinical recommendations on behalf of the European Society of Sexual Medicine. Methods: Medline and Embase databases were searched for randomized clinical trials (RCTs), meta-analyses and open-label prospective or retrospective studies investigating the effect of LISWT on ED, PD, or CP/CPPS. Outcomes: The panel provided statements on clinically relevant questions concerning LISWT: (i) treatment efficacy, (ii) treatment protocol, (iii) clinical indications, and (iv) safety. The level of evidence was provided according to the Oxford 2011 criteria and graded using the Oxford Centre for Evidence-Based Medicine recommendations. Results: 11 RCTs and 5 meta-analyses investigated LISWT for ED. RCTs provided controversial results on the efficacy of LISWT and were affected by high heterogeneity and the small number of patients included. Pooled-data analysis showed an overall positive effect in terms of erectile function improvement but reported small estimates and included a largely heterogeneous cohort of patients. 4 RCTs and 1 meta-analysis assessed LISWT for PD. All trials showed positive findings in terms of pain relief but no effect on penile curvature and plaque size. Inclusion criteria vary widely among studies, and further investigation is needed. 5 RCTs investigated LISWT for CP/CPPS. Data showed a possible effect on pain relief, although there is no evidence supporting that pain relief was maintained or any improvement in pain over time. Clinical implications: LISWT needs to be further investigated in the context of sexual medicine and is almost but not yet ready for clinical practice. Strengths and limitations: All studies have been evaluated by a panel of experts providing recommendations for clinical practice. Conclusions: LISWT is a safe and well-tolerated procedure but its efficacy for the treatment of ED is doubtful and deserves more investigation. Patients reporting pain associated with PD may benefit from LISWT, although no effect is expected on disease progression. LISWT is not a primary treatment for CP/CPPS, but it may be considered as an option to relieve pain. Capogrosso P, Frey A, Jensen CFS, et al. Low-Intensity Shock Wave Therapy in Sexual Medicine-Clinical Recommendations from the European Society of Sexual Medicine (ESSM). J Sex Med 2019;16:1490-1505.
Article
Erectile dysfunction (ED) is defined as the inability to attain and maintain erection of the penis sufficient to permit satisfactory sexual activity. ED most commonly affects men from 40 years of age with a clear age-associated increase in prevalence. The condition may have significant negative impact on quality of life for both the patients and their partners. Over recent years, low-intensity shockwave therapy (LIST) has gained popularity in the treatment of ED, based on the assumption that LIST application may result in neoangiogenesis and thus increased blood flow to the corpora cavernosa. The increasing usage of LIST is contrasting with current guidelines, with the EAU guideline on ED stating that LIST can be used in mild organic ED patients or poor responders to PDE5I’s, but with a weak strength of recommendation. In the AUA guideline on ED, the panel makes a conditional recommendation of grade C that LIST should be considered investigational. In this review, we will briefly review practice patterns, and critically discuss the evidence based on which these guideline statements have been made.
Article
Our interim analysis of a phase II clinical trial on low-intensity extracorporeal shockwave therapy (Li-ESWT) for men with erectile dysfunction (ED) has demonstrated it is safe with no reported adverse outcomes. Interim analysis has demonstrated Sexual Encounter Profile 3 (ability to maintain erection till completion) was achieved in 60% of men prior to Li-ESWT, which increased to 90% after treatment. Nevertheless, limitations of our clinical trial include the lack of a sham arm and our inability to exclude men with psychogenic ED. We have begun recruitment of our phase III clinical trial that will allow assessment of treatment efficacy against a sham control arm. There exists substantial interest in the use of restorative therapies (i.e., Li-ESWT, stem cells, and platelet rich plasma) for men with ED with the potential to combine therapies to potentially lead to an augmented response.
Article
Objective: To use systematic review and meta-analysis to assess the efficacy of low-energy extracorporeal shockwave therapy (LI-ESWT) for erectile dysfunction (ED) was undertaken with a meta-analysis to identify the efficacy of the treatment modality. Methods: A comprehensive search of the PubMed, Cochrane Register and Embase databases to March 2017 was performed for randomized controlled trials reporting on patients with ED treated with LI- ESWT. The International Index of Erectile Function (IIEF) and the Erection Hardness Score (EHS) were the most commonly used tools to evaluate the therapeutic efficacy of LI-ESWT. Results: There were 9 studies including 637 patients from 2005 to 2017. The meta-analysis revealed that LI-ESWT could significantly improve IIEF (mean difference [MD]: 2.54; 95% CI, 0.83-4.25; p= 0. 004) and EHS (risk difference[RD]: 0.16; 95% CI, 0.03-0.28; p = 0.01)). Therapeutic efficacy could last at least 3 mo (MD: 4.15; 95% CI, 1.40-6.90; p =0.003). Lower energy density(0.09mj/mm(2), MD: 4.14; 95% CI, 0.87-7.42; p = 0.01) increased number of pulses (3000 pulses per treatment, MD: 5.11; 95% CI, 3.18-7.05, p < 0.0001) and shorter total treatment courses( <6 weeks, MD: 3.73; 95% CI, 0.54-6.93; p = 0.02) resulted in better therapeutic efficacy. Conclusions: These studies suggest that LI-ESWT could significantly improve the IIEF and EHS of ED patients. The publication of robust evidence from additional RCTs and longer-term follow-up would provide more confidence regarding use of LI-ESWT for ED patients.